The transdermal administration of narcotic analgesics, i.e. opioids, for the treatment of both acute and chronic pain has been described in great detail. The following U.S. Pat. Nos. 4,466,953; 4,470,962; 4,588,580; 4,626,539; 5,006,342; 5,186,939; 5,310,559; 5,474,783; 5,656,286; 5,762,952; 5,948,433; 5,985,317; 5,958,446; 5,993,849; 6,024,976; 6,063,399 and 6,139,866 describe various ways of transdermally administering fentanyl and analogs thereof, such as alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentanil and the like, and are incorporated herein by reference. These patents disclose that fentanyl can be administered from a topically applied ointment, cream, or from a transdermal patch.
The potential for abuse of narcotic analgesics by intranasal, oral or parenteral routes is well known. Diversion and abuse of opioids may take several different forms. For example the medication may be used by a person for whom it is not intended, i.e., diversion, or in amounts and/or frequency greater than prescribed, either by the originally prescribed route (e.g., oral or transdermal) or by an alternate route (e.g. parenteral, intravenous, or intranasal). In order to prevent abuse of these substances, it has been proposed to provide dosage forms which combine the abusable substance with an amount of an antagonist for the abusable substance sufficient to eliminate the “high” associated with abuse of the substance without eliminating the other therapeutic benefits for which the drugs are intended to be administered. See, for example, U.S. Pat. Nos. 3,773,955; 3,493,657; 4,464,378; 4,457,933; 4,626,539; 4,806,341; 4,935,428; 5,149,538; and 5,236,714; and International Publication No. WO 01/58451A1, all of which are incorporated herein by reference. See also, Talwin; Levine J. D., et al, “Potentiation of pentazocine analgesia by low-dose naloxone”, J Clin Invest 1988; 82:1574-1577; Crain S M, Shen F-K, “Antagonist of excitatory opioid receptor function enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability”, Pain 2000; 84:121-131, which are incorporated herein by reference.
U.S. Pat. No. 5,236,714 describes transdermal dosage forms for delivering narcotic and psychoactive substances, the dosage form having a reduced potential for abuse. The transdermal dosage forms comprise an analgesic reservoir comprising a narcotic and an antagonist, and a releasing means through which the narcotic is released to the body. U.S. Pat. No. 5,149,538 describes a misuse-resistive dosage form for transdermal administration of opioids. The dosage form comprises an opioid, an antagonist for the opioid that is releasable upon ingestion or solvent immersion, a barrier means separating the opioid from the antagonist and a delivery means for delivering the opioid.
Notwithstanding some success, the existing dosage forms have not been entirely satisfactory for reducing the potential for abuse, since the narcotic can be extracted from the dosage form for injection, inhalation or ingestion; or the narcotic and antagonist may interact resulting in adverse physical and/or chemical interaction, such as undesirable ion exchange or permeation of the antagonist into the narcotic reservoir resulting in systemic delivery of the antagonist. Upon prolonged exposure to skin, the antagonist elicits a sensitization response. Further, the existing dosage forms do not provide for the controlled release of the antagonist at a rate sufficient to provide an abuse limiting release rate ratio of the antagonist to the narcotic when the dosage form is subject to abuse, e.g., upon ingestion or substantial immersion of the system in a solvent. When such dosage forms are subjected to abuse, the antagonist may be isolated at a rate disproportionate to the release rate of the analgesic from the dosage form, such that the opioid effects of the analgesic are insufficiently blocked during abuse situations.